Evidence suggests that serotonin may play a role in the pathogenesis of developmental disorders, but no specific defect in a serotonergic mechanism has yet been identified. The proposed project will evaluate serotonergically-mediated physiological responses in the CNS and periphery in male children and/or young adults with autistic disorder versus age- and gender-matched normal controls and nonautistic subjects with cognitive impairment. Our pilot study, which included 7 male autistic young adults and 7 normal controls, revealed blunted fenfluramine-induced prolactin release in autistic subjects, a result which suggests decreased central serotonergic responsivity. The mean serotonin-amplified platelet aggregation response, mediated by the platelet 5-HT2 receptor sites. Among autistic subjects, fenfluramine- induced prolactin release correlated positively with the serotonin- amplified platelet aggregation response and negatively with whole blood serotonin content. Correlations between central and peripheral serotonergic measures suggest possible systemic alterations in serotonergic function in autism. The specific aims of the proposed project are to determine: 1) whether central serotonergic responsivity and function of the platelet 5-HT2 receptor complex differ in autistic versus normal subjects; and 2) whether any observed alterations in serotonergic measures in autistic subjects are specific to a diagnosis of autism versus the presence of cognitive impairment. Central serotonergic responsivity will be assessed by neuroendocrine challenge testing (adults only), with prolactin secretion serving as the dependent measure; fenfluramine, an indirect serotonin agonist, will serve as the challenge agent in the initial phase of the study, while challenge studies with a direct 5-HT1 and/or 5-HT2 receptor agonist will be added in a later phase to evaluate receptor function. The prolactin response to TRH will be used to rule out alterations in the secretory capacity of the lactotroph. Studies of platelet 5-HT2 receptor function (children and adults) will include measurement of: 1) the magnitude of serotonin-amplified platelet aggregation; and 2) receptor binding indices. The serotonin content of whole blood and plasma will also be determined. Systematic study of serotonergic responses in autistic persons may not only identify functional alterations in the serotonergic system, but suggest new strategies for pharmacologic treatment.